Two Drugs Kill Resistant Melanoma Cells In Preclinical Study

COLUMBUS, Ohio – Combining a well-known biologic agent with a new targeted anticancer drug triggers the death of melanoma cells that are resistant to therapy, according to an animal and laboratory study by Ohio State University Comprehensive Cancer Center researchers.

This research shows that combining the biologic therapy interferon-alpha (IFNa) with the drug bortezomib causes melanoma cells to self-destruct by the biochemical process of apoptosis. The drug combination significantly increased survival in a mouse-tumor model, and it cut the growth of transplanted human tumors by half in a second model. The study marks the first time the two drugs have been used together for this disease.

The combination even killed melanoma cells that had high levels of two important survival proteins, Bcl-2 and Mcl-1, that block the process of cell self-destruction.

The findings, published in a recent issue of the journal Cancer Research, led to a phase I clinical trial now in progress testing the safety of the drug combination in humans.

Melanoma is the most deadly form of skin cancer. It is expected to strike 62,500 Americans in 2008 and cause 8,400 deaths. The disease is highly curable when treated early, but only 10 to 15 percent of patients with advanced melanoma live more than five years.

“Advanced melanoma is highly resistant to most chemotherapy drugs, so it is particularly important to investigate new combination therapies for this disease,” says principal investigator Dr. William E. Carson, III, a surgical oncologist, melanoma specialist and leader of the cancer center’s innate immunity research program.

“Our preclinical data indicates that the anti-tumor effects of this combination are better than either agent alone, and we observed no significant side effects, suggesting that this may be a good treatment strategy for melanoma and possibly other cancers.”

Bortezomib inhibits the action of proteosomes, complexes in cells that break down proteins. IFNa, approved by the Food and Drug Administration for the treatment of melanoma, increases the sensitivity of melanoma cells to self-destruction.

“We found that the two drugs synergistically activate complementary cell-death pathways and overcome the usual mechanisms that make melanoma cells resistant to standard therapies,” says first author Gregory Lesinski, assistant professor of internal medicine and a researcher in the innate immunity program. Millennium Pharmaceuticals, Inc., provided the bortezomib used in this study.

Funding from the Harry J. Lloyd Charitable Trust; The Melanoma Research Foundation; The Valvano Foundation for Cancer Research Award; the National Cancer Institute supported this research.